We are pleased to submit this revised competing grant renewal examining the basic physiology of vascular drug delivery. This work has taken on renewed urgency in the clinical and fundamental scientific domains. Drug eluting stent systems (DES) are paradigmatic examples of local vascular therapy, and the dramatic reduction of clinical restenosis by DES has led to overwhelming adoption. Yet, early enthusiasm is now tempered by concerns for late blood vessel toxicity from hypersensitivity reactions, delayed vascular healing, incomplete re-endothelialization, and thrombosis. The apparent tradeoff of restenosis for catastrophic complications has heralded an outcry to curtail severely the clinical use of DES until efficacy can be coupled with safety. Risk factors for clinical complications remarkably mirror events we have observed in our preclinical animal models. Tissue response to applied drugs correlates best with local drug penetration, retention and distribution. But this is not a static pharmacokinetic issue alone. The distribution patterns of rapamycin and paclitaxel, the two drugs used on clinically available DES, are dependent upon ultrastructural aspects of target vessels;flow over and through vessels, systemic and environmental states, as well as physico-chemical properties of individual drugs. These distributions evolve over time and with intervention and drug exposure. The clinical relevance is profound. We recently analyzed seven clinical trials that purportedly showed disparate findings with different DES and found a unifying theme in lesion extent and composition. Rapamycin and paclitaxel-eluting stents behaved similarly in native vessels with simple lesions, but their efficacy and side- effect profile widened as lesions became more tortuous, constrictive and heterogeneous. Differences in distribution may explain this effect. These issues provide a natural evolution of the next series of studies. As an extension of our previous work, we will determine the impact of arterial composition, geometry and ultrastructure on drug distribution and drug effect. This unified specific aim draws in multiple aspects of increasingly directed work. We will in this fashion examine (1) how drug uptake differs across different arteries on a bulk tissue level;in vascular compartments;and transmurally, from lumen to adventitia (2) how tissue components &cells serve as physical diffusion barriers AND as specific binding elements (3) the evolution of effect of locally administered drugs over time, and with &(4) vascular morphologic heterogeneity, remodeling, interventional modification and response to disease (5) the impact of flow imposed by vessel geometry &mechanical intervention, on drug distribution effect (6) and finally integration of the above studies with conceptual and mathematical models that further drive design of experiments and formulation of hypotheses. The evolving notions of the interplay of composition, geometry, and ultrastructure and tissue state on local delivery may well clarify the challenges with locally delivered compounds. NIH funding has enabled us to contribute to understanding the interplay between local transport phenomena and vascular repair. This knowledge has helped define the limits and potential of local drug delivery. We have developed a quantitative framework for characterizing the unique patterns of drug distribution that arise within the arterial wall after local drug delivery. We now seek to understand how drug distribution and effect are determined by ultrastructural aspects of target vessels, flow through vessels, and systemic and environmental states, as well as physico-chemical properties of individual drugs.